The Biological Significance of Long noncoding RNAs Dysregulation and their Mechanism of Regulating Signaling Pathways in Cervical Cancer

Despite the remarkable decrease in cervical cancer incidence due to the availability of the HPV vaccine and implementation of screening programs for early detection in developed countries, this cancer remains a major health problem globally, especially in developing countries where most of the cases and mortality occur. Therefore, more understanding of molecular mechanisms of cervical cancer development might lead to the discovery of more effective diagnosis and treatment options. Research on long noncoding RNAs (lncRNAs) demonstrates the important roles of these molecules in many physiological processes and diseases, especially cancer. In the present review, we discussed the significance of lncRNAs altered expression in cervical cancer, highlighting their roles in regulating highly conserved signaling pathways, such as mitogen-activated protein kinase (MAPK), Wnt/β-catenin, Notch, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways and their association with the progression of cervical cancer in order to bring more insight and understanding of this disease and their potential implications in cancer diagnosis and therapy.

promised to offer more insights to our understanding of human physiology and resolving human genetic diseases including cancer (4). Thus, the encyclopedia of DNA elements (ENCODE) project that took over after human genome project completion, deciphered the obtained sequences and provided more in-depth data and analyzed the regulatory elements within the genome (5). Among the biggest discoveries of ENCODE is that the noncoding part of the genome which was described as junk DNA is mostly transcribed into functional RNA molecules, named non-coding RNAs (ncRNAs) (6). This part of the genome is not fully characterized despite the numerous studies on ncRNAs, providing an enormous field of genomics that is yet to be explored.
Several hypotheses are suggested regarding the role of ncRNAs, but their role in gene regulation is well discussed as they influence gene expression without DNA sequence alterations (7). Emerging findings report that lncRNAs, with tissue-specific expression, are involved in diverse cellular and physiological pathways including cell differentiation, maintaining cellular homeostasis, regulation of the immune response to disease, differentiation, and DNA damage repair (8,9).
During malignancy, aberrant expression of lncRNAs is reported in many cancers, suggesting their role in the modulation of the physiological and molecular changes occurring in the transformed cells (9). Evidence from previous researches indicates that lncRNAs mainly interact with proteins, RNA, and DNA and function at transcriptional, translational, and post-translational levels (10). Moreover, Khalil et al. have reported that more than 20% of lncRNAs bind to the polycomb repressive complex 2 (PRC2) and other chromatin modifiers suggesting that chromatin modification might be a common mechanism of lncRNAs action (11).
In cervical cancer, an increasing number of functional studies have reported that dysregulation of the expression of diverse lncRNAs is involved in the regulation of malignant progression. In fact, the abnormal expression patterns of lncRNAs often correlate with the development and progression of cancer and play a crucial role in cell proliferation, invasion, and metastasis (12)(13)(14). LncRNAs exert their functions in CC mainly through the regulation of gene expression, which appears to be mediated by different processes such as chromatin state modulation and RNA processing (15). In CC, a number of lncRNAs showed abnormal expressions, such as HOX antisense intergenic RNA (HOTAIR), plasmacytoma variant translocation 1 (PVT1), and growth arrest specific 5 (GAS5), which are associated with disease progression and poor prognosis (16)(17)(18). On another hand, growing interest is given to the role of lncRNAs in viral replication and pathogenesis supporting their involvement in the host-pathogen interaction and suggesting the initiation and promotion of associated diseases (19,20). In the present review, (MAGI2-AS3) that were also widely considered as specific biomarkers for early diagnosis (21)(22)(23)(24)(25)(26).
Studies on the different mechanisms and interactions of lncRNAs with other genes and proteins that confirm the involvement of lncRNAs in CC development and progression are summarized in Table 1. and enhanced cell proliferation in CC (24). This oncogenic treat has been reported in other recent studies confirming that MAGI2-AS3 promotes other cancers types such as colorectal and gastric cancers (45,46). On the other hand, GAS5 was reported as a tumor suppressor lncRNA. Its ectopic overexpression induced cell cycle arrest at G2/M checkpoint which is mediated by the inhibition of cyclin B1 and CDK1 expression by GAS5. Elevated expression of BAX and suppression of BCL-2 is also a consequence of GAS5 overexpression, which ultimately induces apoptosis (22).
LncRNA MALAT1 was previously reported to be highly expressed in CC cells, and was correlated with cancer progression and metastasis (47).
Recent data suggest that HPV E6/E7 and IL-6/STAT3 signaling pathways work synergistically to up-regulate the transcription of MALAT1 in CC HeLa cells, suggesting the cooperation of the virus oncoproteins with cellular inflammatory signaling in CC development (49).

Involvement of lncRNAs in signaling pathways
When Wnt is not expressed, cytoplasmic βcatenin is degraded by a protein complex composed     (12,105,106).
Of particular interest, most lncRNAs are up-regulated to sponge microRNAs and control cancer- Up-regulated miR-125b STAT3 Up-regulated miR-508-3p RGS17

RHPN1-AS1
Up-regulated miR-299-3p FGF2 Down-regulated miR-155  They also found that these altered lncRNAs interacted with mRNAs that appear to play key roles in key cellular processes such as DNA repair, cell death, response to stimuli among others, all of   (206). In addition, ROC curve analysis demonstrated that OIS1 could potentially be used as a diagnostic marker for HPV positive but not for HPV negative cervical squamous cell carcinoma (207).
Interestingly, it was found that damage induced noncoding (DINO) lncRNA could restore the function of TP53 in CC. The reactivation of TP53 by DINO increases the vulnerability of CC to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress, which suggests that this lncRNA could be used as a therapeutic alternative to the existing unsuccessful approaches (201).

Conclusion
The field of research on lncRNAs is growing